Principal Investigator/Program Director (Last, First, Middle):Kottmann, Andreas H. Abstract: Functional and/or structural corruption of the ascending, mesencephalic dopaminergic system is prominent in many neuropsychiatric and neurodegenerative disorders including schizophrenia, Parkinson's disease, attention deficit disorder, drug addiction, depression, and anxiety. A complete understanding of the trophic support mechanisms that lead to the maintenance of the dopamine system in the adult brain might aid in the development of novel strategies for the management of these diseases. Sonic hedgehog, Shh, is expressed in mesencephalic, dopaminergic neurons in the adult mouse brain. Shh, a morphogen, which controls many aspects of ontogeny, orchestrating congruent growth and patterning, also takes part in the regulation of cell survival in many tissues. The genetic ablation of Shh specifically from dopaminergic neurons, which we achieved through the expression of the recombinase Cre controlled by the dopamine transporter (Dat) locus, leads to viable and active animals. However, we observe a progressive deficit in locomotion activity and a reduction of the numbers of both, dopaminergic (DA) neurons in the substantia nigra pars compacta and cholinergic (ChAT) neurons in the striatum, at 12 weeks of age. The objective of this explorative project is to determine whether ablation of shh from dopaminergic neurons (1) leads to a progressive functional and structural corruption of the SNpc and/or striatum in the adult mouse (2) influences the resilience of DA neurons to neurotoxic insults (3) influences the regenerative capacity of DA neurons after neurotoxic insults We expect that work funded through this grant will lead to a novel neurodegenerative disease model. PHS 398/2590 (Rev. 09/04) Page Continuation Format Page Principal Investigator/Program Director (Last, First, Middle):Kottmann, Andreas H. Narrative: Functional and/or structural corruption of the ascending, mesencephalic dopaminergic system is prominent in many neuropsychiatric and neurodegenerative disorders including schizophrenia, Parkinson's disease, attention deficit disorder, drug addiction, depression, and anxiety. The genetic ablation of Shh specifically from dopaminergic neurons, which we achieved through the expression of the recombinase Cre controlled by the dopamine transporter (DAT) locus, leads to a progressive deficit in locomotion activity and a reduction of the numbers of both, dopaminergic (DA) neurons in the substantia nigra pars compacta and cholinergic (ChAT) neurons in the striatum, at 12 weeks of age. Work funded through this grant seeks to determine whether this animal paradigm is a novel neurodegenerative disease model. PHS 398/2590 (Rev. 09/04) Page Continuation Format Page [unreadable] [unreadable] [unreadable]